New antibacterial compounds



United States Patent Ofiice Patented July 25, 1961 The present invention relates to new antibacterial compounds. More particularly the compounds with which the invention is concerned correspond to the following generic formula:

wherein X represents a sulfur atom or a vinylene group CH=CH.

The compounds of this invention have been found particularly useful against a series of gram-positive and gram-negative bacteria. They were tested against 35 species of bacteria and fungi in fluid medium. The bacterial sensitivity tests on most strains were carried out in Penassay broth Difco. The tests on M. flavus, S. hemolyticus, D. pneumoniae and Brucella abortus were carried out in Brain Heart Infusion Difco. The Myc. tuberculosis H37Rv strain was tested in Proskauer-Beck medium having the following composition: Asparagine g., KI-I PO 5 g., K 50 0.5 g., glycerol 20 ml., trimagnesium citrate 1.5 g., H 0 800 ml., horse serum 100 ml. The paratubercular strains were tested in TB broth base with 5% glycerol and Dubos medium albumin. The antifungal tests were made in Sabouraud medium of the following composition: peptone 10 g., dextrose 40 -g., H 0 1000 ml. The minimal inhibiting concentrations in ug./ml. are expressed in Table I. The readings were made after 18 hrs. for bacteria and 40 hrs. for fungi.

TABLE I Spectrum of antibacterial and antimycotic activity [Minimum inhibitory concentration ,ugJmL] (1) 2-bromo-4- (2) a-Bromo-B- cyano-cinnamal- (5-cyano-2-thidehyde enyD-acrolein M. aureus l0 5 5 5 10 10 Sir. hemolyticus 10 10 Streptococcus faecalis 20 20 B111. pneumoniae 2 10 E 02' 10 20 10 20 20 50 2O 50 5 10 5 1O 50 10 10 5 5 5 5 10 5 5 10 5 10 10 2O 10 Myc. 607 10 2O Myc. tuberculosis H37Rv 5 5 Nocardia asteroides 10 5 Sacchar. cercvisiae 0. 5 1 K Zoeckera brevis 0. 5 0. 5 Candida albicans ATCC 1023 5 5 Candida albicans SKF 2270.. 5 5 Cryptococcus moformzms- 1 2 Aspergzllus niger 20 20 Penicillium sp 5 2 Hisioplasma capsulatum- 0. 5 0. 5 Trich. memagr. AICC 8757 0. 5 2 Trick. mentagr. SKF 17410 2 0. 5 irichophyton schoenleini. 2 1 Trichophg/ton cutaneum 2 1 The compounds were tested also on experimental animals and found very active. Furthermore their toxicity was found to be very low, ranging between 700 and 1000 rug/kg. in mice, rats and rabbits on administration by oral route, and between 200 and 350 mg./kg. by intraperitoneal route.

The topical use of the compounds of the invention on humans was successful, giving substantial improvement in most skin infections due to the organisms reported in Table I. The compounds were applied in the form of ethyl alcohol solutions containing 1 mg./ml. or in ointments containing l10% of the active ingredient incorporated in one or more of the common ointment bases, such as Vaseline, lanolin, etc.

The method for preparing the compounds of the invention starts from 4-cyanobenzaldehyde or from 5-cyano-2- thiophenecarboxaldehyde. While 4-cyanobenzaldehyde is already known in the chemical literature, 5-cyano-2- thiophenecarboxaldehyde has been prepared by us from Z-methyl-S-iodothiophene which with cuprous chloride in alkaline medium is transformed into S-cyano-Z-thiophenecarboxaldehyde as described in one of the examples of the present application. Cyanobenzaldehyde or cyanothiophenecarboxaldehyde are then refluxed with acetaldehyde in the presence of acetic anhydride for about one hour; on cooling, the condensation product precipitates, i.e. 4'- cyanocinnamaldehyde or B(5-cyano-2-thienyl)-acrolein. These compounds are converted into the other compounds of the generic formula by introduction of an halogen into position a.

The a-bromination is carried out under particular conditions. By treatment with one mole of bromine saturation of the double bound occurs with formation of the oe,,8-dibromoderivative. This latter is treated with an alkali metal carbonate without isolating it from the reaction medium, whereby the desired a-bromoacrolein is obtained.

This invention is illustrated by the following examples which, nevertheless, are not intended to limit the same.

EXAMPLE I A mixture of 20 g. 5-iodo-2-methylthiophene, 190 cc. anhydrous pyridine and 14.3 g. cuprous cyanide is refluxed for 8 hours. The pyridine is then distilled ofi in vacuo, the residue is extracted with ethyl acetate, the extract is dried and after evaporating the solvent in vacuo the residue is fractionated, the product being collected at 87 C. under 1 mm. Yield 8.5 g. (77%) of S-cyano- Z-methylthiophene, 11 1.565.

To a mixture of 13.5 g. 5-cyario-2-methylthiophene, 171 cc. glacial acetic acid and 169.5 cc. acetic anhydride, 25.5 cc. concentrated sulfuric acid are slowly added, without exceeding 25 C. followed by 30 g. chromic anhydride, added at small portions and keeping the temperature between 5 and 10 C. The mixture is stirred for some minutes, then it is poured in about twice its volume of ground ice. The light yellow precipitate is collected in vacuo and dried. Yield 18 g. (69%) of 5- cyano-Z-thiophenecarboxaldehyde diacetate, M.-P. 77- 78" C.

To a mixture of 140 cc. ethyl alcohol, 140 cc. water and 35 g. 5-cyano-2-thiophenecarboxaldehyde diacetate, 10.5 ml. concentrated sulfuric acid is quickly added, then the mixture is refluxed till a complete solution results (about 20 minutes). On cooling, 5-cyanofl-thiophenecarboxaldehyde precipitates which is collected in vacuo, washed with water and dried. Yield 18 g. (90%); MP. 93-94 C.

A mixture of 34.2 g. 5-cyano-2-thiophenecarboxaldehyde and ml. acetaldehyde is cooled between 6 and 8 C., and at this temperature 5 ml. of a 25% potassium hydroxide solution in anhydrous methanol are added. After addition of 100 ml. acetic anhydride the mixture is refluxedfor one hour, then it is cooled, a solution of 35 ml. concentrated hydrochloric acid in 300 ml. of water is added, the mixture is again refluxed for 30 minutes and cooled. The precipitate is washed with water and recrystallized from water. Yield 27 g. (66%) ofB-(S- cyano 2-thieny1)-acrolein, M.P. l28-129 C.

To a solution of 94 g. B-(S-cyano-Z-thienyl)-acr olein in 720 cc. of glacial acetic acid, kept at a temperature between 33 and 35 32 ml. of bromine are added in small portions. To the obtained solution 40 g. potassium carbonate are gradually added. 'When the addition is complete the mixture is refluxed for 30 minutes. On cooling, u-bromo-fl-(-cyano-2-thienyl)-acrolein' precipitates which is collected in vacuo and recrystallized from 95% ethyl alcohol. Yield .116 g. (83%); M.P. 153- 155 C.

.EXAMPLE 2 To a solution of 32.7 g. 4-cyanobenzaldehyde in 100 ml. acetaldehyde, previously cooled.at-6-7' C., 5 ml. of 25% potassium hydroxide in anhydrous methanol are slowly added. After addition oflOO m1. acetic anhydride the mixture is refluxed for 30 minutes. On cooling white crystals mixed with some resin precipitate. 'The mixture is filtered and the solids recrystallized from 1% acetic acid. Yield 27 g. (69%) 4-cyanocinnamaldehyde, M.P. l35-137 C.

To a solution of 30 g. 4'-cyanocinnamaldehyde in 240 ml. glacial acetic acid previously heated to 35 C., 10.5 ml. bromine are added dropwise. When the addition is complete, 13.2 g. anhydrous potassium carbonate are added and the mixture is refluxed for 30 minutes. After cooling the crystals are collected in vacuo and recrystallized from anhydrous ethanol. Yield 42 g. (94%) of 4-cyano-x-bromocinnama1dehyde, M.P. 156-157 C.

We claim:

1. A compound of the formula wherein X is a member of the class consisting ofa sulfur atom and the vinylene group.

2. a-Bromo-4'-cyanocinnamaldehyde.

3. a-Bromo-,8(5-cyano-2-thienyl)-acrolein.

4. A pharmaceutical composition for combatting topical bacterial and fungal infections, comprising from about 0.1 to about 10% of a compound of the formula wherein X is a memberof the class consisting of sulfur and the vinylene group, and a physiologically acceptable diluent.

5. A pharmaceutical composition for combatting topical bacterial and fungal infections, whose active component consists essentially of a compound'of the formula References Cited in the file of this patent UNITED STATES PATENTS Carrara July 16, 1957 OTHER REFERENCES Blank: AMA. Arch. of Derm., February 1957, vol. 75, No. 2, pp. 184492.

Frazier: Ext. Therapy of the Skin, Chas. Co. Thomas, publisher, Springfield, Ill. (1954), p. 81.

Reiss et al.: J. Invest.-Dermat., vol. 24, N0. 6, June 1955, pp. 575-577. 

4. A PHARMACEUTICAL COMPOSITION FOR COMBATTING TOPICAL BACTERIAL AND FUNGAL INFECTIONS, COMPRISING FROM ABOUT 0.1 TO ABOUT 10% OF A COMPOUND OF THE FORMULA 